| The association between body constitution and disease is one of the key scientific issues in the subject of traditional Chinese medicine(TCM)constitution.In April 2009,the publication of Classification and Determination of Constitution in TCM provided a recognized and standardized measurement tool for clinical research on the association between constitution and disease.Therefore,by using this standard,the number of clinical studies published in the past decade has grown rapidly from scratch.These studies have important value for understanding the correlation between constitution and disease,and promoting the application of constitution in the prevention and treatment of diseases.However,there is still no systematic study of the existing clinical research literatures,nor comprehensive study on clinical research methodology of TCM constitution.What are the bibliometric characteristics of these existing studies? What kind of body constition and disease do the studies focus on? What are the findings on the relationship between body constitution and disease? What are the implications of these studies for clinical practice? What is the methodological quality of the studies? How to conduct a high-quality clinical study to explore the constitution-disease relationship? etc.For these issues,no related papers have been published yet.Therefore,this study attempted to systematically study and analyze the above problems by means of bibliometric analysis,systematic review,and theoretical research.1 Objective(1)Analyze the bibliometric characteristics,research contents,results and methodological quality of included studies,summarize and evaluate the characteristics,laws and trends of constitution-diesease clinical study at home and abroad,and introduce the current research findings on the correlation among various TCM constitution types and diseases.(2)Taking metabolic syndrome(MS)as an example,through systematic review of clinical research,analyze the constitution distribution characteristics of MS patient and the correlation between constitution and MS based on a larger population,thus provide higher level evidence for disease prevention and treatment,and demonstration for conducting systematic review of clinical studies on constitution-disease relationship in the future.(3)Analyze the specificity and methodological challenges of clinical research on constitution-disease relationship,propose methodological recommendations for the design,implementation and reporting of clinical studies,and provide reference for improving the quality of constitution-disease clinical research,in order to promote the generation of more high-quality evidence on constitution-disease study.2 MethodsPart one(Bibliometrics research): China National Knowledge Infrastructure(CNKI),Wanfang Data,CQVIP,PubMed and Embase database were searched from April 1,2009(the publication date of CCMQ)to December 31,2018.All observational studies including cross-sectional study(CSS),case-control study(CCS),and cohort study(CS)on constitution-disease relationship were included.The bibliometric characteristics,research content,results and methodological information were extracted from the fulltext of included studies.For methodological assessment,the standard of Agency for Healthcare Research and Quality(AHRQ)was applied in CSS,and Newcastle-Ottawa Quality Assessment Scale(NOS)was applied in CCS and CS.Descriptive statistical methods were employed for data analysis.Part two(Systematic review): Systematic review was used to conduct in-depth analysis on the clinical study of constitution-disease relationship by taking metabolic syndrome(MS)as an example.The distribution of TCM constitution of MS patients and its risk for the occurrence of MS were explored by meta-analysis.Methods of literature search,inclusison criteria and quality evaluation were the same as Study I.R 3.5.2 software was applied for the meta-analysis of rate,and Reviewer Manager 5.3 software was applied for the comparison of constitutional distribution between MS patients and the general population.Funnel plot analysis was used to dectect potential publication bias.Part three(Methodological research): Based on the Study I and Study II,literature research,theoretical research,and expert consultation were integrated for methodological study on constitution-disease relationship.From the perspective of clinical epidemiological research ideas,this paper analyzed the characteristics of TCM constitution research,and proposed suggestions for improving the implementation and report quality of constitution-disease clinical research.3 ResultsPart one: A total of 1441 observational studies on constitution-disease relationship were included,with a total sample size of 858,271 cases.The study covered 29 provinces(autonomous regions),Taiwan and Hong Kong of China,and other countries including Malaysia,South Korea,Singapore,Thailand,and France.313 diseases were studied,covering 19 disease categories of International Classification of Diseases-10(ICD-10).The most studied diseases included hypertension,diabetes,stroke,coronary heart disease,insomnia,dysmenorrhea,breast cancer,chronic hepatitis B,fatty liver disease,osteoporosis,etc.Cross-sectional study was the most popular study design,accounting for 90.2%(1300/1441)of all studies,and CCS and CS were 81 and 60,respectively.Distribution of disease spectrum of various TCM constitution type: 1)qi-deficiency constitution is highly distributed in diseases such as diabetes,cerebral infarction,AIDS,chronic obstructive pulmonary disease,coronary heart disease,sub-health,insomnia,chronic fatigue syndrome,chronic hepatitis B,and breast cancer.2)yang-deficiency constitution is highly distributed in the distribution of infertility,osteoporosis,irritable bowel syndrome,knee osteoarthritis,dysmenorrhea,polycystic ovary syndrome,menopausal syndrome,rheumatoid arthritis,and recurrent miscarriage.3)yin-deficiency constitution is highly distributed in diseases such as hypertension,diabetes,constipation,climacteric syndrome,osteoporosis,dry eye,lung cancer,recurrent stroke,and insomnia.4)phlegm-dampness constitution is highly distributed in hypertension,fatty liver disease,diabetes,MS,stroke/cerebral infarction,coronary heart disease,dyslipidemia,hyperuricemia,polycystic ovary syndrome,obesity/overweight,and sleep apnea hypopnea.5)damp-heat constitution is highly distributed in acne,hyperuricemia,chronic gastritis,asthenozoospermia,eczema,hepatitis B,constipation,cholelithiasis,hypertension,and gout.6)qi-stagnation constitution is highly distributed in breast hyperplasia,breast cancer,insomnia,depression,premature ovarian failure,migraine,glaucoma,infertility,hyperthyroidism,thyroid nodules,and adenomyosis.7)blood statis constitution is highly distributed in coronary heart disease,endometriosis,and stroke.8)inherited special constitution is highly distributed in allergic diseases such as asthma and allergic rhinitis.Distribution of diseases prone to various TCM constitution type: 1)People with qi-deficiency constitution have a relative higher risk of obesity,diabetes,chronic fatigue syndrome,anxiety,etc than non qi-deficiency constitution people.2)People with yang-deficiency constitution have a relative higher risk of osteoporosis,obesity,cervical spondylosis,chronic fatigue syndrome,etc.3)People with yin-deficiency constitution have a relative higher risk of hypertension,osteoporosis,diabetes,etc.4)People with phlegm-dampness constitution have a relative higher risk of cerebral infarction,hypertension,obesity,hyperlipidemia,diabetes,MS,etc.5)People with damp-heat constitution have a relative higher risk of constipation,high blood pressure,etc.6)People with qi-stagnation constitution have a relative higher risk of sub-health,menopausal syndrome,osteoporosis,anxiety,breast cancer,breast hyperplasia,dysmenorrhea,etc.7)People with blood statis constitution have a relative higher risk of osteoporosis,stroke,hypertension,hyperlipidemia,etc.8)People with inherited special constitution have a relative higher risk of asthma.Methodological quality: CSS of high,medium,and low quality accounted for 4.6%,90.8%,and 4.6%,respectively;CCS of high,medium,and low quality accounted for 27.2%,51.9%,and 21.0%,respectively;CS of high,medium and low quality accounted for 28.3%,58.3% and 13.3%,respectively.The results of quality control,confounding factors control and response rates were poorly reported in the majority of included studies.Part two: A total of 23 observational studies on the constitution-disease relationship of MS were included in 21239 cases,including 13393 patients with MS and 7846 control participants.Of the 23 studies,3 were CCS and 20 were CSS.The three major constitutions of MS patients were phlegm-dampness [30%(22%-39%)],qi-deficiency [20%(15%-26%)] and damp-heat [14%(11%-18%)].The odds ratio(OR)of phlegm-dampness for the occurrence of MS was 1.75(95% CI: 1.17-2.62),and 3.46(95% CI: 2.14-5.59)after adjusting for confounding factors.The OR of qi-deficiency for MS was 1.39(95% CI: 1.04-1.85).The proportion of phlegm-dampness and damp-heat constitution in male patients was 1.19 and 2.10 times that of female patients,respectively,and the proportion of qi-deficiency in female patients was 1.32 times that of males.MS patients under the age of 45 had the highest proportion of phlegm-dampness,qi-deficiency constitution and damp-heat cosntitution among all groups.Two cross-sectional studies were of high quality;20 cross-sectional studies were all of medium quality.The funnel plot analysis showed that the literature was scattered around with obvious asymmetry,suggesting the existence of publication bias and study heterogeneity.Part three: Clinical research on constitution-disease relationship was an observational study with its particularity.To carry out a high-quality research,some methodological challenges needed to be faced: Firstly,the application of observational studies in TCM was less,and the methodological study was lagging behind;secondly,the study of constitution-disease relationship was affected by a variety of confounding factors,and the influence of constitution on disease ran through the whole process of disease;thirdly,the particularity of constitution,including subjectivity and dynamic variability,made the perform of clinical study on constitution-disease relationship facing methodological challenges.CSS,CCS and CS have their application scope in clinical studies of constitution-disease relationship.There are also different in evidence level for revealing the association or causal relationship between constitution and disease.The design type should be selected according to study purpose and conditions.During the implementation phase of the study,new cases of disease with typical constitution are recommended for inclusion,and sample size calculation should be reported.The collection of baseline data information should be comprehensive and quantitative.Constitution measurement should attach great importance to quality control to ensure accurate results.Statistical analysis of data should use a multivariate analysis method to control the impact of confounding factors on the results.Conclusions on the correlation between constitution and disease should be drawn with caution.The international guidelines and standards of quality evaluation and reporting guidelines for observational research are universal,and most of the items are applicable to the evaluation and reporting of clinical studies on constitution-disease relationship.According to the characteristics of clinical research on constitution-disease relationship,this study attempted to improve relevant items based on the existing standards and guidelines,so as to provide reference for formulating the implementation and reporting standards of clinical research on constitution-disease relationship.4 ConclusionGreat achievements have been made in clinical research on constitution-disease relationship in the past decade.These studies fully verified the scientific nature of TCM constitutional theory,finding that some constitutions were closely related to relevant diseases,which provided an important basis for the application of body constitution identification in TCM and public health practice.Systematic review could help to produce high-level evidence for understanding the relationship between constitution and disease,also provide references for TCM treatment based on differentiation of constitution,syndrome and disease.To carry out clinical research on constitution-disease relationship,under the premise of following the internationally recognized principles and relevant standard norms of clinical research,it is necessary to fully consider the particularity of constitution.Researchers should select appropriate design types according to their objective,and pay attention to quality control throughout the whole process of research.The reporting of study should follow the STROBE statement and reflect the characteristics of TCM constitution.Finally,this paper proposes some improvement suggestions for the quality evaluation and reporting norms of clinical research on constitution,in order to provide guidance for the conduction and publication of high-quality research,so as to promote the application of TCM constitution in disease prevention and treatment. |
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